Methods and apparatus for preparing autologous blood eye drops

ABSTRACT

Methods and apparatus for preparing autologous blood serum eye drops within a potentially contaminating environment are disclosed. Key convenience kit apparatus providing novel methodology includes a plastic bag in which an innovative tray securely holds a plurality of empty eye drop bottles and associated caps disposed and sealed therein. Providing the only access pathway into the bag is a sterilizing filter appliance which filters all fluid entering the bag and provides a nozzle for dispensing into bottles disposed in the tray. The key convenience kit apparatus is sterilized prior to use, assuring all components disposed within the bag are within a desired sterility assurance level. The sterilized state of items associated with the key apparatus is maintained by the single pathway for fluid. Capping and sealing the bottles before opening the bag permits delivery of sterile product for use outside the bag.

CONTINUATION-IN-PART

This Patent Application is a CONTINUATION-IN-PART of U.S. patent application Ser. No. 16/501,534 filed Apr. 25, 2019 by Gale H. Thorne, et al. and titled METHODS FOR PREPARING AUTOLOGOUS BLOOD EYE DROPS which is a CONTINUATION-IN-PART of Ser. No. 16/350,279 filed by Gale H. Thorne, et al. (Thorne 279). Oct. 25, 2018 and titled CONVENIENCE KITS FOR ASEPTIC STERILIZING AND DISPENSING.

FIELD OF INVENTION

This invention relates generally to methods for medical procedures involving liquid transfer, sterilization and mixing in a field environment to produce a sterile autologous blood eye drop product. It is also particularly related to kits and to methods which employ preassembled parts to provide a sterile product without requiring confines of a laminar flow hood.

BACKGROUND AND DESCRIPTION OF RELATED ART

Conventionally, mixing and formulation of medications is a pharmacy or other medical environment performed function most often involving use of laminar flow hoods and strict aseptic technique to maintain sterility. In pharmacies, medical solutions are often passed through a medical grade sterilizing filter to assure an aseptic condition. Resulting products from these facilities are highly regarded and widely used in hospitals and other clinical facilities.

However, today, a significant portion of medical practice takes place outside sophisticated medical institutions. As an example, a new and very effective eye-treatment technology is based upon mixing autologous blood serum with normal saline in exacting proportions. Commonly, blood is drawn from patients in a wide range of areas remote from pharmacies and laboratories. The expense and inconvenience of relying on such facilities to sterilize and mix is prohibitive, negatively affecting broader application of this promising technology. Thus, there exists a severe contemporary need for a process or methodology, not currently available commercially, which can, with appropriate safety and efficacy, provide such sterilizing, dispensing and mixing to produce sealed containers of autologous blood eye drops in a field capability.

Convenience kits have become commonly used appliances for a number of reasons. First, a convenience kit is specifically made for a given application. Contents of each such kits are prepared and provided in a form which generally reduces procedure steps and improves efficiency. Second, such kits can provide additional safety such as the kit disclosed in U.S. Pat. No. 9,449,521, titled METHODS FOR MAKING AND USING A VIAL SHIELDING CONVENIENCE KIT, issued May 28, 2013, which proved effective in providing additional safety to technicians and patients by keeping hazardous drug fumes and liquid fully contained.

Vial and bottle filling into containers disposed within a plastic bag is also known in medical art. An example of such a process is provided in U.S. Pat. No. 9,140,939, allowed Oct. 6, 2015 to Jean-Pascal Zambaux (Zambaux) titled DISPOSABLE ISOLATOR COMPARING MEANS FOR FILLING CONTAINERS. However, the process, as disclosed in Zambaux, has been abandoned in the United States due to experience of contamination in source liquid used for filling without further sterilization. Such contamination has been found to be in liquid distributed to a plurality of containers, resulting in a spread of infection. For this reason, the Applicants understand that compounding pharmacies are now commonly employed for filling medical vials and bottles through sterilizing filters. Relative to the instant method of the current invention, Zambaux is also deficient for being used for a portable all environment convenience kit because no method for capping and thereby protecting sterile state of liquid in bottles and vials is taught.

As indicated supra, use of sterilizing filters in now well known and accepted. U.S. Pat. No. 9,636,444 titled FILTRATION SYSTEM FOR PREPARATION OF FLUIDS FOR MEDICAL APPLICATIONS allowed to Jeffrey H. Burbank, et al. (Burbank) allowed May 2, 2017 discloses such use, but, as is the case of Zambaux, does not disclose filling and capping within a bag to protect a sterile state when removed there from.

Terms and Definitions

Following is a list of terms and associated definitions which are provided for clarity and understanding when used to disclose precepts of the instant invention:

contaminating environment, n: substance surrounding comprising freely moving masses which communicate with an unshielded substance to negatively affect the substance SAL

dead space, n: a volume of inaccessible fluid which is retained within a device after a procedure

digital, adj: relating to, or done with thumb or fingers

distal, adj: a distance relative to a cited object or person; opposite of proximal

ETO, n: acronym for ethylene oxide, a powerful sterilizing agent

field of use, n: a location in an uncontrolled environment in which potentially contaminating health-hazardous materials are present.

filter, n: a product material having a sufficiently small porous matrix to impede passage there through of a particulate of predetermined size; a medical grade sterilizing filter generally has a 0.2 micron pore size

filter assembly, n: apparatus comprising one or more filters and a sealed bag interface

filter component, n: A housing for a filter having a pair of opposing fittings providing communicating conduits to and from the filter.

fitting, n: a medical connector

insulated wrap, n: a flexible container which may be a bag or folded shield which is sealed to provide a container in which enclosed parts can be maintained at a reduced temperature

kit, n: a group of parts, provided within a single package for a designated use laminar flow hood, n: (a fume hood) a work-place enclosure in which purified air flow is directed so as to prevent contamination of sterile materials by airborne organisms. It should be noted that special training and technique is required to prevent contamination by such physical manipulations as touch and breathing. luer fitting, n: a medical connector having a frustoconical-shaped connecting geometry which is in common use in medical practice luer lock fitting, n: a luer fitting having a locking mechanism whereby a male and female connector are securely, but releasably affixed one to the other plastic bag, n: a sturdy container made of clear pliant material which comprises an opening initially available at one end for product insertion and which is sealed thereafter to provide a totally enclosed product shroud, the material being sufficiently pliant to permit digital, in-bag product handling from outside the container interface gasket, n: an elongated hollow tube that is sized, shaped and disposed to be affixed to along a filter component conduit about a hole in a plastic bag and thereby provide a fluid tight seal between the bag and component conduit gasket support, n; a rigid component which has an outer diameter which is similar to an outer diameter of a gasket and an inner diameter which interfaces with a luer connecting fitting to thereby transfer force from the connecting fitting to an interface gasket to provide a seal port or portal, n: an orifice site where through fluid is communicated (generally associated with a conduit sealingly disposed there through) proximal, adj: an indicator of a segment of a device being normally closest to an object of a sentence describing its position radiation, n: generally gamma radiation imposed with sufficient intensity and time to sterilize a product to a desired SAL. SAL n: Sterilized Assurance Level sub-kit, n: a group of parts provided as a unit and considered to be a kit when provided alone but a lesser kit form when provided as a part of a more inclusive kit which is packaged with additional items tray, n: a convenience kit container wherein kit parts are stored and transported; for the case of the current invention the tray is considered to provide a special interface with kit parts unitized, adj: a plurality of separate parts permanently joined to be handled and used as a single unit

BRIEF SUMMARY AND OBJECTS OF THE INVENTION

In brief summary, this novel invention alleviates all of the known problems related to mixing, dispensing and providing a sterile liquid product for delivery into a field environment. It is important to note that preparation of autologous blood eye drops simply involves mixing a measured volume of patient serum with a volume of normal saline determined by prescribed serum/saline concentration and acquired patient serum volume. Though other methods may be employed within the scope of the instant invention, preferred devices and processes are disclosed hereafter for clarity of enablement.

Commonly, medical products, as mentioned supra, are often produced by being sterilized by filtration and mixed under a fume or laminar flow hood in a pharmacy or laboratory facilities. For products which are acquired for sterilizing and mixing in a field environment, remote from such facilities, lack of a fume hood or laminar flow capability currently prohibits wide-spread production of autologous blood eye drops. It is for the purpose of fulfilling this need that an inventive methodology based upon a novel sub-kit is disclosed herein.

The core items of this sub-kit are a conventional commercial plastic bag, having an accessible opening, which is closed and sealed after sub-kit assembly, a sterilizing filter assembly which is affixed to the bag via a sealed portal to provide a solitary sterilizing fluid pathway to components inside the so closed bag and a tray for providing bottle containment and retention throughout the eye drop preparation process. To assure product sterility, the bag and articles are sterilized after assembly and prior to use. Once sterilized, the only passageway inside the sealed bag is through the filter assembly. Therefore, all product inside the bag remains sterile for all subsequent procedures until the bag is opened.

Generally, the preferred embodiment of the filter assembly comprises a first sterilizing filter comprising a body which holds and surrounds a filter part to provide for fluid flow only through the filter. The filter body also comprises a pair of opposing conduits which provide a pathway to and from the filter. One of the conduits with a male Luer fitting (the internal conduit) is disposed through a hole in the bag and sealed thereat to assure retention of a predetermined SAL within the bag. A sealing grommet, disposed about the conduit and bag hole is affixed to assure competence of the seal. A nozzle part may be affixed to the end of the internal conduit for directing liquid flow there through. The preferred embodiment also comprises a second sterilizing filter, having similar structure to the first filter, serially securely, but releasably affixed outside the bag to the first filter (e.g. via a male/female Luer fitting interface). It has been commonly demonstrated that. when delivering volumes of particulate contaminated liquid (as derived from a biological source) a first filter can clog and obstruct flow. Under such conditions, no further flow is possible through the first filter resulting in kit failure due to flow obstruction. Providing a second filter cascaded with the first filter aggregates clogging material in the second filter. Thus, when flow is obstructed by clogging, the second filter can be removed and, if necessary, replaced.

For the instant invention, the sub-kit is delivered as part of a larger kit which may additionally comprise two empty conventional medical syringes having male luer fittings, a female/female luer fitting component which is affixed to one of the two empty syringes, a blood collection tube transfer barrel and an accessible volume of normal saline (preferably provided as pre-filled saline syringes). All of the additional parts may be provided clean, rather than sterile as all fluid which passes into the plastic bag is sterilized by passing through the filter which provides the only entry pathway into the bag. Note that all parts of both the sub-kit and larger kit meet a current FDA Convenience Kit Standard which requires all components involved with a medical procedure be previously approved for medical use.

An exemplary, more detailed description of components of the sub-kit made according to the instant invention may be as follows:

1. The plastic bag is sufficiently supple and impenetrable to permit digital manipulation of items disposed therein via digital contact only with the bag exterior and has an accessible opening for displacement of the articles into the bag before the opening is closed and sealed, sufficient material disposed about the opening to permit sealing and an exterior surface which completely envelopes and protects sterility of articles disposed therein. Bag and articles therein should be predisposed to digital manipulation via the bag exterior and should be radiation stable.

2. A filter component comprising at least one sterilizing grade filter (and preferably two cascaded filters (a first filter and a second filter) each having two opposing elongated conduits having connecting fittings at ends remote from each filter housing. One of the conduits of the first filter, is displaced through a tight fitting hole in the bag. A gasket seal is disposed about the conduit/hole interface, providing a hollow conduit as the only fluid access pathway into the bag after the bag opening is sealed. Note that the pathway leads to at least one filter through which all fluid must pass, thereby assuring that no non-sterile material can be introduced into the bag beyond the filter.

3. At least one bottle comprising an open orifice provided for dispensing eye drop liquid there through.

4. A cap for each at least one bottle, the cap being able to be affixed to the bottle while in protective enclosure of the bag to provide a protective seal about the bottle orifice, such that when attached to the bottle and thereafter removed from the bag, following liquid transfer, product sterility is assured. As cap to interior bag surface may not have an exterior surface frictional interface which promotes easy digital access and handling within the bag, each cap is provided with a treatment about a grasping surface which increases the coefficient of friction between bag and cap and thereby permits facile digital displacement of each cap.

5. A tray having cavities for each bottle and associated cap. The bottle cavities are sized and shaped to securely engage the bottles during transport and kit displacement and to strictly restrict bottle rotation while caps are affixed thereto. Further, the cavities are disposed to affix retention forces at each bottle bottom permitting bottles to be “popped” free after the tray is displaced from the bag. Similarly, cap cavities are sized and shaped to retain each cap until digitally accessed for capping a bottle while having retaining forces disposed at the bottom thereof to permit each cap to be “popped” free for easy access.

One of the compelling purposes for basic convenience kits resulting from this invention is providing fluid flow through a sterilizing filter. As liquids to be mixed in a field environment can be expected to be compromised and/or contaminated, it is critical that every so-employed liquid be passed through such a filter and sterilized while being displaced into the bag. In the case of the instant invention, retention of sterility throughout dispensing is extremely important. For this reason, all kit mixing, sterilization and subsequent packaging functions are performed within the plastic bag which retains such sterility until reopened. It is important to note that digital facility of kit use is also very important. As a consequence, it is preferred to use a bag which comprises a snap or peel open seal for access after product transfer and sealing in capped bottles. However, it is not enough to maintain liquid sterility only while the product is inside the bag. The product must be shielded and disposed in a closed and sealed container before being displaced from the bag.

Given the sub-kit contents and additional parts which make up the larger kit, the method for preparing autologous blood eye drops is as summarized in table 1, below:

TABLE 1 Step # Step Comment 1 Using conventional procedures, acquire (It is currently preferred to draw a predetermined volume of blood from blood into evacuated tubes (such as a a patient for which a prescription has Becton Dickenson Corporation been provided for receiving eye drops Vacutainers ™). made according to the instant invention. 2 Separate serum from other blood Centrifuging is the preferred method components 3 Collect serum into a single container in A preferred method for collecting is which the total volume of available accomplished by connecting a blood serum can be measured collection tube transfer barrel to an empty syringe (hereafter referenced as the “serum syringe”). These items and other non-sub-kit items are provided as part of the larger kit mentioned supra. 4 After collecting all serum from the Eye drop dose determination (i.e. evacuated tubes, measure the amount amount of serum acquired to be mixed of serum collected and determine with a predetermined volume of saline volume of normal saline to mix with to yield a prescribed concentration of a the serum. blood/serum mixture for a given patient prescription) will likely vary from procedure to procedure, therefore, it is necessary to determine both volume of serum available and amount of saline to be used. The amount of saline to be added to the blood can be calculated using a novel dosing chart, disclosed herein or by equation also provided hereafter. 5 Displace, for delivery, the determined It is preferred to draw the required volume of normal saline into a volume from the larger kit provided measurable container. pre-filled saline syringes into the originally empty syringe affixed to a female/female connector (hereafter referenced as the saline syringe). 6 Mix the collected serum with the Mixing is preferably accomplished by measured volume of saline transferring all of the contents of the saline syringe into the serum syringe and then displacing contents of the two syringes back and forth at least three times, ending with all of the contents disposed within one syringe defined to be the dispensing syringe. 7 Access the sub-kit. The sub-kit is preferably packaged in a separate casing for safety assurance 8 Prepare sub-kit for use If the second filter is capped, remove cap. To align the tray with the filter assembly, grasp the exposed portion of the filter and displace it upward relative to the tray, thereby centering the tray. Note: All fluid entering the bag is filtered so the SAL state of the bag is not challenged and the filter will not pass gas once wetted. 9 Deliver a desired volume of the mixture 11. Separate the saline and serum into the filter assembly through the syringes and affix the dispensing cascaded filters into each bottle syringe to the second filter fitting for sterilizing the mixture by delivering through the cascaded filters. Note: Suppleness of the bag permits digital direction of the filter assembly nozzle (spout) toward each targeted bottle orifice 10 Displace and offset the filter assembly Once the bottles are filled, the filter and syringe away from the tray such assembly parts internal to the bag are that bottle caps can be digitally displaced away from the tray to permit accessed. capping of the bottles. 11 Cap each bottle Each cap is individually digitally accessed via the bag exterior. A surface treatment of the cap provides a sufficiently frictional interface between cap and bag to permit each cap to be “popped” from the tray and affixed to an associated bottle. Preferably, each cap is affixed to the bottle by a threaded attachment requiring cap rotation relative to a bottle which is kept stationary by being snugly held within a cavity of the tray. 12 Breach the bag to access the sealed Once the bottles are capped and so bottles sealed, the eye drop product is protected when displaced into a contaminating environment. Thus the bag can be breached with safety, permitting access to individual bottles.

To show by example, a comparison of advantages and disadvantages relative to employing a convenience kit used according to the present invention versus using a laminar flow hood, for a sterile transfer process, distinctions are summarized in the following two tables (i.e Tables 2 & 3).

Table 2 summarizes a comparison of general factors related to preparing an eye-wash product using a laminar flow hood and the convenience kit.

TABLE 2 Parameters Laminar Flow Hood Present Invention Number of packages 15  1 to open Filter .2 micron - small tip .2 micron - high flow Maintenance of sterility Technique All items in bag and dependent entering bag are pre- sterilized - virtually impossible to contaminate accidentally Likelihood of product Low Remote contamination Receiving vessel Usually no special A stabilizing receptacle stability stabilizers used can be provided within the bag Injection into receiving Filtered liquid Sterilized by filter vessels through a before dispensing filtered air stream into a sterile field User steps 42 24 Ease of use Simple with proper Simpler with conventional training technique

Table 3 compares a current process of producing an eye treatment product to a like product production using a convenience kit made according to the present invention.

TABLE 3 Present Parameters Conventional * Invention * Open Packages 15 1 Set up receiving vessels 4 0 Draw serum into syringe 9 9 from vacutainers Purge air from syringe 1 1 Draw saline into delivery 3 3 syringe Mix 1 1 Attach filter to syringe 1 1 Dispense into four receiving 4 4 vessels Cap vessels 4 4 Total 42 24 * Steps to change filters not included

Accordingly, it is a primary object to provide convenience kit methods and apparatus for transferring and sterilizing mixed eye drop liquids to, thereby, provide a packaged, sealed, aseptic product which can be produced in a potentially contaminating environment.

It is a major object to provide a kit which can be used to sterilize, mix and protectively seal, for safety, a sterilized product for delivery into a contaminating environment without use of a laminar flow hood.

It is a principle object to provide methods for a portable apparatus which can be used for preparing and delivering prescribed concentration eye drops sterilized to a predetermined SAL within a contaminating environment.

It is an object to provide methods and apparatus for preparing and using convenience kits which can be used for sterilizing and delivery of autologous blood-based eye drops in home care situations.

It is a very important object to provide a kit and methods, for sterilizing liquids to be dispensed into bottles within an internally sterile kit, by which contaminating particles are filtered before entry into a sterile field and for assuring aggregated particles do not prematurely clog the first filter and prematurely impede or obstruct bottle filling.

It is an object that the sub-kit comprises a sectioned bottle and cap holding tray which has at least two cavities wherein eye drop bottles and caps are disposed and securely affixed therein for eye drop liquid dispensing and bottle capping whereby bottles are filled and capped in a sterile state within a plastic bag before distribution into a non-sterile environment.

It is a fundamental object to provide a bag which is sealable for maintaining contents sterile therein and able to be opened for access to products mixed and sterilized therein.

It is another major object that bagged parts of a convenience kit made according to the present invention be digitally accessible and displaceable such that liquid sterility protecting caps can be securely affixed to vessels before perforating the bag barrier.

It is yet another critical object to select items which are gamma stable for purposes of sterilization within the bag.

It is still another object to provide a means for transporting and storing filled eye drop bottles in a controlled environment for stability of product sterility and medical efficacy.

These and other objects and features of the present invention will be apparent from the detailed description taken with reference to accompanying drawings.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a perspective of an exemplary tray made according to the instant invention with cavities of predetermined shape and size filled with caps and bottles which are examples of items employed for filling and capping eye drops to preserve sterility thereof.

FIG. 1A is a perspective of a perspective of an assembled key kit made according to the instant invention, the kit comprising a first filter appliance, a portion of which is seen disposed outside a plastic bag, items enclosed within the bag being the tray seen in FIG. 1 securely holding a plurality of bottles and bottle caps.

FIG. 1B is a perspective of another embodiment of an assembled key kit which is the same as the key kit seen in FIG. 1B except that a second filter appliance is affixed to the first filter appliance such that filtering by the two filter appliance is cascaded.

FIG. 2 is a perspective of the plastic bag and filter appliance parts, seen in FIG. 1B, but before assembly, the bag having an open end and a filter component seen to be disposed outside the bag and associated filter appliance and bag sealing components with an assembly tool disposed within confines of the bag.

FIG. 2A is a perspective of a section of tubing for use as a sealing interface gasket having predetermined length and internal diameter relative to the filter component seen in FIG. 2

FIG. 2B is a perspective of a segment of the bag seen in FIG. 2 with a portion of a filter component having pierced the bag and disposed snugly within a hole formed therein.

FIG. 3 is a perspective of a segment of the bag seen in FIG. 2, similar to the segment seen in FIG. 2B, with a portion of a filter component disposed outside the bag and another portion disposed through an unseen orifice disposed in the bag (but unseen) with components affixed to the inside portion to seal about the orifice.

FIG. 4 is a perspective of a bottle to be disposed within the tray seen as in FIGS. 1 and 1A.

FIG. 5 is a perspective of a cap for closing and providing a seal to protect contents of the bottle seen in FIG. 4.

FIG. 6 is a perspective of the tray seen in FIG. 1 with a plurality of empty cavities.

FIG. 7 is a perspective of a bag comprising an affixed filter appliance as seen in part in FIG. 1A and a tray filled with bottles and caps and disposed within the bag, with the open end seen in FIG. 2, closed and sealed.

FIG. 8 is a perspective of a plurality of evacuated tube blood draw vessels (e.g. Becton Dickinson Vacutainers™).

FIG. 9 is an exploded perspective of an evacuated tube blood draw vessel seen in FIG. 8 and a tube access barrel used to mete out blood or blood constituents from the vessel.

FIG. 10 is a perspective of separate items used in a larger kit to support the key kit.

FIG. 10A is a perspective of a combination of a medical syringe seen in FIG. 10 affixed to an evacuated tube access barrel wherein a blood draw tube is inserted for selectively accessing blood constituents.

FIG. 11 is a cross section of the conventional medical syringe seen in FIG. 10A, comprising a measurable volume of liquid accessed from one or more blood draw vessels.

FIG. 12 is an exemplary “dosing” chart comprising indicia from which a desired volume of saline can be derived for mixing with predetermined volume of serum for producing a dose of eye drops.

FIG. 13 is a perspective of a conventional syringe affixed to a female/female fitting (as seen in FIG. 10) and thereby affixed to a pre-filled syringe for acquiring saline.

FIG. 13A is a cross section of the medical syringe seen in FIG. 13 with a predetermined volume of saline disposed therein.

FIG. 14 is a perspective of the syringes seen in FIGS. 11 and 13 affixed together via the female/female adapter.

FIG. 14A is a cross section of the syringes seen in FIGS. 11, 13 and 14 with all liquid dispensed into a single syringe and a double arrow disposed to indicate relative displacement of syringe pistons for mixing.

FIG. 15 is a perspective of the assembled key kit, seen in FIG. 1, with the filter appliance upwardly disposed to center the tray disposed therein and to “tent” the bag thereby disposing the filter appliance for dispensing liquid into the bottles.

FIG. 15A is a perspective of upwardly displacing and “tenting” the bag similar to the method seen in FIG. 1, but employing an additional hand to aid in centering the associated tray.

FIG. 16 is a perspective of the assembled key kit, seen in FIGS. 15 and 16, with the syringe seen in FIGS. 10 and 11 containing a serum/saline mixture and affixed to the filter component of the filter appliance for dispensing liquid into bottles thereby.

FIG. 17 is a perspective wherein a bottle cap is digitally accessed for removal from the tray for being affixed to a bottle (into which a predetermined volume of serum/saline mixture has been dispensed).

FIG. 17A is a perspective wherein the bottle cap digitally accessed in FIG. 17 is being digitally affixed to a bottle.

FIG. 18 is a perspective of bottles securely capped for protecting sterility of mixture disposed therein, thus permitting safety in displacing the bottles from the plastic bag.

FIG. 19 is a perspective of an insulated pouch for storing and transporting capped bottles after displacement from the plastic bag and then the tray and plastic bag as seen in FIG. 18.

FIG. 20 is a perspective of a “freezer pack” used to maintain a desired temperature inside the pouch seen in FIG. 19.

DETAILED DESCRIPTION OF THE ILLUSTRATED EMBODIMENTS

Reference is now made to the embodiments illustrated in FIGS. 1-20 wherein like numerals are used to designate like parts throughout. For parts which are similar but not the same in form and function as parts originally specified with a given number, a prime of the original numbers is used.

This inventive method is specifically dedicated to preparing autologous blood serum eye drops. While inventive properties disclosed may be applied throughout a wide variety of applications, the following description is singly focused on eye drop production.

Kit Preparation Steps

In FIG. 1, a tray 2 is seen wherein a plurality of eye drop bottles, each generally numbered 4, are disposed within cavities, generally numbered 5, and associated bottle caps, generally numbered 6, are disposed in cavities, generally numbered 7. Tray 2 is a key element of the instant invention providing a stabilizing base for transport and securing bottles 4 and caps 6 as disclosed in detail hereafter.

Reference is now made to FIG. 1A wherein an assembled convenience kit 10 made according to the instant invention is seen. A preferred clear plastic bag 20 is seen to completely envelope a plurality of bottles 4 and associated caps 5 disposed and restrained in a tray 2. To be ready for use, kit 10 has been sterilized to a predetermined SAL. A filter appliance 50 has been disposed through a singular hole in bag 20 (not seen in FIG. 1A). Filter appliance 50 comprises a filter component 60 and the only fluid access path 70 into bag 20. Filter component 60 is preferred to be a 0.2 micron sterilizing filter which assures that all fluid displaced along path 70 is sterilized to a predetermined SAL, thereby assuring everything within bag 20 remains sterile in any environment until bag 20 is opened. Filter components, such as filter component 60 are widely used and commercially available for sterilizing fluids in contemporary medical practice.

However, filtering of biological materials, such as serum, yields a wide variety of particles and other separated products which must be retained within the filter component to produce a filtered product sterilized to the predetermined SAL. The unpredictable nature and bulk can clog to produce sufficient obstruction to flow that an undesirable pressure is required to continue dispensing through filter component 60. Such obstruction of filter component 60 is catastrophic to device such as kit 10, which depends upon continued flow for proper performance. For this reason, a second filter component 60′ is securely, but releasably affixed to filter component 60 to cascade flow through both filters, as seen in FIG. 2. As such filter component 60′ becomes a collector of filtered debris with only filtered liquid being displaced through filter component 60. Thus, when filter component 60′ is obstructed, removal or removal, with replacement, of filter component 60′ permits continued use of kit 10 in production of eye drops.

Reference is made to FIG. 2 wherein a sequence for assembling filter appliance 50 to bag 20 is seen. Therein, filter component 60 is seen to comprise a female luer fitting 80, an increased radius housing 82, which contains the 0.2 micron filter (not shown), and a male luer fitting 84.

As seen in FIG. 2B, male luer fitting 84 comprises a distal end 84′ which is diminished sufficiently in size to permit fitting 84 to pierce bag 20 forming a hole 85, therein, about fitting 84. Material characteristics of plastic bag cause hole edges to reluctantly give way, resulting in hole 85 circumference 85′ snugly fitting about fitting 84 with no laterally extending tear.

Also as seen in FIG. 2B, disposed directly below fitting 84 is a section 86 of tubing sized and shaped to provide a gasket about the hole through which fitting 84 is disposed and about fitting 84. Cylindrical shape of tubing section 86 is seen in FIG. 2A. A female luer fitting 88, as shown in FIG. 3, is disposed directly below tubing section 86. Female luer fitting 88 is disposed to force an integrally molded, superiorly disposed shoulder ring 89 (see FIG. 2) compressively against tubing section 86 (as seen in FIG. 2B) such that tubing section 86 acts as a gasket against the hole in plastic bag 20 which is to be formed by piercing bag 20 and disposed to surround fitting 84. Preferably, fitting 88 is adhesively affixed to fitting 84. An assembly tool 90 (see in FIG. 2) comprising a patterned hole 92 for stabilizing fitting 88 is preferably used when fitting 84 as displaced into fitting 88 for attachment. A fully assembled filter appliance 50 is seen in FIG. 3 disposed through a hole in a segment 20′ of bag 20.

Referring once more to FIG. 2, the second filter component 60′ is affixed to filter component 60 by insertion of male fitting 84 of component 60′ into female fitting 80 of component 60, being conventionally interconnected. Note that this interconnection can be disconnected for removal of filter component 60′ and, if desired another filter component can be thereby replaced.

Selection of an effective eye drop bottle is critical to the safety and effectiveness of the instant invention. As such, the eye drop bottle must be able to be securely capped and closed to preserve sterility while still being disposed within bag 20. Also, because a prolonged period of time (e.g. four to six weeks) may pass from time of mixing and bottle filling until use, a desired product SAL must be maintained until use. In addition, as the eye drops are used at a prescribed rate, eye drop accuracy and precision is important. For this reason, an eye drop bottle (called Novelia® (Novelia)) commercially available from Nemera, an international company originated in France, is preferred for use in products made by the instant invention. Nemera states the following concerning Novelia:

-   -   Preservatives have been shown to be harmful to the eye and can         lead patients to discontinue or skip treatment to avoid         irritation and discomfort. The new multidose ophthalmic         packaging Novelia avoids the need for preservatives in the drug         by preventing contamination of unpreserved formulations. Novelia         represents a major innovation in ophthalmic drug delivery by         providing a preservative free alternative for chronic treatments         in a patient friendly package. Novelia has been well accepted by         patients in over 45 countries worldwide, including U.S.,         European, Latin American and Asian countries. It is used for         packaging drug products as well as medical devices. The key         benefit for patients is that it can be used as a ‘classic’         multidose eyedropper. This device is able to calibrate droplets,         which improves compliance. Its blue tip allows better precision         when targeting the eye and bottles are easy to squeeze. Novelia         is also more sustainable and affordable than unit-doses, and         easier to carry.     -   For ophthalmic pharmaceutical companies, Novelia offers major         advantages:         -   30% controlled and safe thanks to patented PureFlow®             technology         -   Functional with emulsions, suspensions and solution up to             high viscosities         -   Compatible with most existing filling lines (screw cap)     -   The key requirement for such a device is microbiological         sterility; Novelia has been tested and confirmed for content         sterility and drop non-contamination for treatment duration (90         days). Novelia represents a major innovation in ophthalmic drug         delivery devices by providing patients with a preservative free         alternative for chronic treatments, with a patient-friendly         package.

Reference is now made to FIGS. 4 and 5 wherein elements of the preferred bottle 4 and cap 6 for the invention are respectively seen. In FIG. 4, eye dropper bottle 4 is seen to comprise an open, superiorly disposed filling orifice 102, a raised thread pattern 104 whereby cap 6 is affixed to bottle 4 and a locking ring 106 whereby cap 6 is securely locked to bottle 4 by continuing rotation about pattern 104. Bottle 4 also comprises a large vessel portion 108 which is sized and shaped to hold a predetermined volume of product.

Cap 6, seen in FIG. 5, comprises two basic sections, a superior section 112 and an inferior section 114. Superior section 112 is formed as a displaceable lid which is attached via a threaded interface (not shown) to section 114. When section 112 is disposed in abutting contact with section 114 and securely affixed to bottle 4, bottle 4 is sealed closed. Cap 6 is rotated about the threaded interface between section 112 and 114 to open bottle 4 for eye drop dispensing as disclosed by Nemera (supra). A locking interface (not shown) within section 114 securely affixes cap 6 to bottle 4 when cap 6 is fully turned about thread pattern 104 (see FIG. 4) and thereby close bottle 4 orifice 102. For purposes, disclosed in detail hereafter, outer surface 115 of section 112 is treated to change the coefficient of friction between surface 115 and bag 20 interior surface.

Reference is now a made to FIG. 6 wherein tray 2 is seen with a plurality of empty cavities generally numbered 5 and 7. Each cavity 5 is sized and shaped to provide inferiorly disposed pressure about an inserted bottle 4. Such inferiorly disposed pressure restricts bottle rotation when cap 6 is affixed to bottle 4. Inferior application of retaining pressure permits bottle 4 to be “popped” free from tray 2 for independent use after being displaced from bag 20. Each cavity 7, similar to cavity 5, is sized and shaped to retain a cap 6 during transport and before being displaced for capping a bottle 2 while being disposed in bag 20. Further, exterior surface 115 (see FIG. 5) is treated with an overcoat of a substance which substantively increase the coefficient of friction between bag 20 inner surface and section 112. Without such treatment the interface between bag 20 and cap 6 would be “slick” making digital grasping difficult, if not impossible to accomplish. With the treatment, digital displacement of cap 6 is made facile and sure, a feature which is critical to the instant inventive method. Tray 2 is seen to be filled with bottles 4 and caps 6 in FIG. 1.

To complete kit 10 assembly, tray 2 filled with bottles 4 and caps 6 is displaced into bag 20 as seen in FIG. 7. Then bag 20 is securely closed by a heat seal 130 to complete assembly as a final assembly step. So closed and sealed bag 20 is sterilized along with all implements of convenience kit 10 contained therein, preferably by gamma radiation. Thus, an enclosed, qualified SAL space, inside bag 20, which is only accessible through sterilizing filter 50 through pathway 70 is created according to the instant invention. Note that filter component 60′ is not seen in FIG. 7 as sterility of component 60′ is not required, making component 60′ a field replaceable component.

Eye Drop Preparation Steps

Blood is preferably accessed from a patient for preparing autologous blood eye drops; using Becton Dickinson Vacutainers™, samples of which are commonly numbered 150 and seen in FIG. 8; by conventional technique.

Items which are provided as part of a larger kit are seen in FIG. 10. These items comprise:

1. A first conventional medical syringe 200 which is specified to have a capacity for accessing and containing the total liquid volume of all vessels 108 of bottles 4 in convenience kit 10.

2. A second medical syringe 210 having the same liquid volume as syringe 200 and having a female/female fitting 212 affixed thereto.

3. A Vacutainer™ access barrel 220.

4. A plurality of conventional pre-filled normal saline syringes, generally numbered 230.

Each of items listed in 1-3, above, can be provided clean (as opposed to sterile) because all fluid which contacts these items is sterilized upon being dispensed through pathway 70 of filter component 60 into bag 20. For the same reasons, filter component 60′ can be provided clean. For safety, prefilled syringes 230 should be pre-sterilized.

Preparation for filling bottles 4 involves:

1. Prescribing a ratio of serum to saline to be mixed and form a desired mixture which is used as autologous blood eye drops.

2, Following conventional procedures for:

-   -   a. Drawing a prescribed volume of blood from a patient         (preferably into evacuated tubes (e.g. Becton Dickinson         Vacutainers™), generally numbered 150, as seen in FIG. 8.     -   b. Separating patient serum from other blood constituents by         centrifuging each evacuated tube 150 and then meting out serum         from other blood constituents. For this procedure, a         conventional evacuated tube access barrel 232 is preferred to be         used (seen in FIG. 9, along with an evacuated tube 150 disposed         for insertion into barrel 232). Separated serum is drawn into         syringe 200 from barrel 232, interconnected, as seen in FIG.         10A.

3. Using conventionally provided indicia (not shown in FIG. 10) on syringe 200 barrel or determining by weight a measure of the volume of patient serum 240 collected in syringe 200 as shown in FIG. 11.

4. Referencing the prescribed saline/serum ratio, determining the amount of saline which must be added to the acquired blood volume to formulate each predetermined dose. Two methods for determining saline volume are currently preferred. However, other methods may be used within the scope of the instant invention. A first method is via a chart 242 such as the one seen, by example, in FIG. 12. As an example, if the dose serum to saline ratio is 20% to 80%, respectively and the measured amount of serum is 8.4 mL, a value of 8.4 is located under the 20% Serum column heading and a straight horizontal line (such as line 244 is drawn from the serum value across to the associated saline value which is, within plotting accuracy, 33.6 mL. If a number processing program, like EXCEL is available the saline volume (mLsal) can be calculated from dose (% ser) and measured serum volume (mLser) by the following equation: mLsal=mLser (100−% ser)/(% ser)

5. Drawing determined required dose volume of saline (mLsal) into syringe 220 (see FIG. 10) from pre-filled syringes 230, resulting in syringe 210 being partially filled with saline 250 as seen in FIG. 13.

6. Affixing syringe 200 to communicate with syringe 210 as seen in FIG. 14, displace contents of syringes 200 and 210 back and forth a predetermined number of times (at least three times is preferred) to assure adequate mixing of serum and saline, with all of the mixture being displaced into a syringe (preferred syringe 200) at the end of the mixing cycle.

7. Detaching filled syringe from fitting 212.

8. Acquiring kit 10, which may be disposed as seen in FIG. 1B, and digitally clutching filter appliance 50, at bag 20 exterior, and displacing appliance 50 upward, as seen in FIG. 15, “tents” bag 20 for more facile access to items disposed within bag 20. A second hand and may be used in the “tenting” process as seen in FIG. 15A for assuring tray 2 centering below filter appliance 50.

9. Then, affixing, as seen in FIG. 18, syringe 200 to filter component 60′ (or filter component 60, if filter component 60′ has been removed) and dispensing a prescribed volume into each bottle 4 via orifice 102 as shown by example in FIG. 16. Note that suppleness of bag 20 permits digitally guiding filter appliance 50 into communication with each bottle 4 whereupon liquid is efficaciously dispensed through each orifice 102.

10. Capping each bottle 4. Once each bottle 4 is filled with a prescribed dose sterilized to a predetermined SAL, perhaps the most important step still remains, capping and sealing each bottle 4 for delivering bottles into an open environment would otherwise likely detrimentally affect SAL of bottle content. To cap each bottle, each cap 6 (see FIGS. 1, 5 and 7) is digitally accessed one-by-one, by external contact through bag 20 as seen in FIG. 17. As stated supra, as molded, cap 6 has an exterior surface 115 which has a very low coefficient of friction, making virgin caps difficult, if not impossible to grasp effectively. To facilitate digital grasping and displacing cap 6, surface 115 should be coated with a material, such as rubbery Plasti-Dip by Plasti-Dip, International. Once each cap 6 is displaced in contact with bottle 4 about orifice 102, suppleness of bag 20 permits twisting cap 6 and thereby securely affixing each cap 6 and sealing each bottle 4. It should be remembered that, for ease of digital operation from the exterior of bag 20, each cavity 5, in which bottle 4 resides in tray 2, is sized and shaped to restrain bottle 4 from turning as cap 6 is rotated into a closing and locking position. Note that it is a design characteristic of Novelia to lock cap 6 to bottle 4 as a final action of cap 6 bottle 4 attachment, resulting in each bottle 4 being securely capped as seen in FIG. 18. Such locking permits section 112 of cap 6 to be later displaced from section 114 for dispensing eye drops.

11. Providing a protected product for use outside bag 20. Once all bottles 4 are filled and capped, bag 20 is accessed for delivering eye drops to a patient, additional care should be provided for, while the product is sterile to a given SAL, the product contains material which is life based. To aid in maintaining at a predetermined SAL, it is highly recommended that a means for keeping eye drop liquids at a low temperature throughout transport and storage. For this purpose, an insulated bag 300 and an associated ice pack 310 (seen in FIGS. 19 and 20, respectively) be provided as part of the larger kit. Such insulated bags and ice pack are commercially available.

The invention may be embodied in many other specific forms without departing from the spirit or essential characteristics thereof. The presently disclosed embodiments are therefore to be considered in all respects as illustrative and not restrictive, the scope of the invention being indicated by the appended claims rather than by the foregoing description, and all changes which come within the meaning and range of equivalency of the claims are therefore intended to be embraced therein. 

What is claimed and desired to be secured by Letters Patent is:
 1. A method for making and using a portable convenience kit for producing autologous blood serum eye drops, sterilized to a predetermined sterility assurance level, dispensed into bottles and sealed closed for delivery into a potentially contaminating environment without using special equipment, such as a controlled, sterilized state workplace in which fluids can be distributed and maintained free from contamination, such as a laminar flow hood, comprising the follow steps: i. providing the convenience kit comprising: a. a plastic bag, comprising an accessible opening for displacement of items therein, being constructed of material which is sufficiently supple and impenetrable to permit digital manipulation from outside the bag of items disposed therein without severing, being constructed with sufficient material disposed about the opening to permit sealing the bag closed and comprising an exterior surface which completely envelopes and protects sterility of articles disposed therein; b. a filter appliance comprising a gasket and a first filter component, each of which comprises two opposing fluid conducting conduits and a sterilizing grade filter disposed to filter all fluid which is displaced between the conduits, one of said conduits being displaced through a hole in said bag which is sealed closed about the inserted conduit by said gasket; c. a combination comprising at least one eye drop bottle and at least one associated cap which when securely affixed to said bottle closes an orifice through which liquid is dispensed and thereby provides secure sterility protection for bottle contents; d. a tray, which provides a plurality of stabilizing support cavities, comprising one cavity for each bottle and for each cap of said combination, each said bottle cavity being sized and shaped to secure an inserted bottle from displacement due to tray transport and rotation when a cap is applied thereto and each said cap cavity being sized and shaped for securing a cap in transport and being disposed for facile digital access from outside said bag; ii. disposing the number of bottles to be filled and associated caps in said tray; iii. affixing said filter appliance to said bag to provide the only fluid pathway into said bag after the accessible opening is sealed; iv. sealing said opening; v. sterilizing said convenience kit to a predetermined sterility assurance level; vi. providing implements for acquiring blood from a donor patient, separating and accessing serum from acquired blood; vii. establishing a ratio of serum volume to saline volume for a prescribed dose; viii. measuring quantity of acquired blood and determining there from the volume of saline to be mixed with the acquired serum to produce the prescribed dose; ix. preparing a measured quantity of saline; x. dispensing and thereby displacing desired sterilized quantities of saline and serum through and from said filter appliance into the bottles; xi. digitally displacing and securely affixing a sealing cap to each bottle; and xii. after all bottles are filled and capped, breaching the bag and extracting bottles containing protected sterile product for use.
 2. A method for making a portable aseptic level assurance convenience kit for producing autologous blood serum eye drops, sterilized to a predetermined sterility assurance level, dispensed into bottles and sealed closed for delivery into a potentially contaminating environment without using special equipment which provides a controlled, sterilized state workplace in which fluids can be distributed and maintained free from contamination, such as a laminar flow hood, comprising the follow steps: i. providing the convenience kit comprising: a. a plastic bag, comprising an accessible opening for displacement of items therein, being constructed of material which is sufficiently supple and impenetrable to permit digital manipulation from outside the bag of items disposed therein without severing, being constructed with sufficient material disposed about the opening to permit sealing the bag closed and comprising an exterior surface which completely envelopes and protects sterility of articles disposed therein; b. a filter appliance comprising a gasket and a first filter component, each of which comprises two opposing fluid conducting conduits and a sterilizing grade filter disposed to filter all fluid which is displaced between the conduits, one of said conduits being displaced through a hole in said bag which is sealed closed about the inserted conduit by said gasket; c. a combination comprising at least one eye drop bottle and at least one associated cap which when securely affixed to said bottle closes an orifice through which liquid is dispensed and thereby provides secure sterility protection for bottle contents; d. a tray, which provides a plurality of stabilizing support cavities, comprising one cavity for each bottle and for each cap of said combination, each said bottle cavity being sized and shaped to secure an inserted bottle from displacement due to tray transport and rotation when a cap is applied thereto and each said cap cavity being sized and shaped for securing a cap in transport and being disposed for facile digital access from outside said bag; ii. disposing the number of bottles to be filled and associated caps in said tray; iii. affixing said filter appliance to said bag to provide the only fluid pathway into said bag after the accessible opening is sealed; iv. sealing said opening; v. sterilizing said convenience kit to a predetermined sterility assurance level; vi. providing a second filter component which comprises fittings for securely but releasably affixing said second filter to said first filter to cascade flow through both filters whereby, when said second filter is so affixed, values of concentration of filterable particulates, nature of particulates to clog a filter and volume of dispensed liquid do not diminish effective duration of kit effectiveness. 